Diabetic autonomic neuropathy (DAN) is a complex, devastating and understudied condition, affecting the quality of life, morbidity and mortality of millions of patients. Clinical presentation, histopathology and presumably electrophysiologic changes in autonomic nerves can occur in isolation or be dissociated from somatic diabetic neuropathy. The current practice of estimating DAN by evaluating the behavior of organs innervated by autonomic nerves is problematic, since these systems are profoundly influenced by multiple factors in addition to neuropathy. The central thesis of this proposal is that it is both feasible and highly desirable to develop a battery of electrophysiologic measures capable of examining multiple facets of neural activity in autonomic nerves, including conduction velocity, response amplitudes, refractory periods and neural fatigue. We propose to adapt electrophysiologic methods that have been successful in recording of CNS activity to measure the slow, non-synchronous signals in autonomic nerves and in the network of largely unmyelinated axons that form autonomic plexuses and ganglia. These novel techniques will be applied to rats with STZ-induced hyperglycemia and Zucker Diabetic Fatty (ZDF) rats, as models of type 1 and type 2 diabetes, respectively. At both early and late time points, the electrophysiologic findings will be correlated with histopathology and morphometric measures of DAN. These parallel studies will provide insight into the onset and progression of functional and structural deficits in autonomic nerves associated with hyperglycemia and will substantially improve our ability to differentiate effective therapies, especially as they impact the autonomic system. The outlined studies are sequential. First we will evaluate technical innovations (eg., novel electrodes, non-linear analyses) to define a useful battery of measures in normal rats; the methods judged optimal will then be diabetic models, and finally used to evaluate the effects of two putative therapeutic interventions (ie., an ARI and lipid soluble thiamine derivative). If successful, these studies will result in new methods, more sensitive animal models and a better understanding of the nature, magnitude, time course, and response to therapy of functional deficits in DAN.